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6ey8
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Estimation of relative drug-target residence times by random acceleration molecular dynamics simulation== | |
| + | <StructureSection load='6ey8' size='340' side='right' caption='[[6ey8]], [[Resolution|resolution]] 2.16Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6ey8]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EY8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EY8 FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C4T:~{N}-[(4-chlorophenyl)methyl]-~{N}-methyl-6-oxidanyl-3-(phenylmethyl)-1~{H}-indazole-5-carboxamide'>C4T</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ey8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ey8 OCA], [http://pdbe.org/6ey8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ey8 RCSB], [http://www.ebi.ac.uk/pdbsum/6ey8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ey8 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/HS90A_HUMAN HS90A_HUMAN]] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.<ref>PMID:15937123</ref> <ref>PMID:11274138</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Drug-target residence time (tau), one of the main determinants of drug efficacy, remains highly challeng-ing to predict computationally and, therefore, is usually not considered in the early stages of drug de-sign. Here, we present an efficient computational method, tau-random acceleration molecular dynamics (tauRAMD), for the ranking of drug candidates by their residence time and obtaining insights into ligand-target dissociation mechanisms. We assessed tauRAMD on a dataset of 70 diverse drug-like ligands of the N-terminal domain of HSP90alpha, a pharmaceutically important target with a highly flexible binding site, obtaining computed relative residence times with an accuracy of about 2.3tau for 78% of the compounds and less than 2.0tau within congeneric series. Analysis of dissociation trajectories reveals features that af-fect ligand unbinding rates, including transient polar interactions and steric hindrance. These results sug-gest that tauRAMD will be widely applicable as a computationally efficient aid to improving drug resi-dence times during lead optimization. | ||
| - | + | Estimation of drug-target residence times by tau -random acceleration molecular dynamics simulations.,Kokh DB, Amaral M, Bomke J, Gradler U, Musil D, Buchstaller HP, Dreyer MK, Frech M, Lowinski M, Vallee F, Bianciotto M, Rak A, Wade RC J Chem Theory Comput. 2018 May 16. doi: 10.1021/acs.jctc.8b00230. PMID:29768913<ref>PMID:29768913</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6ey8" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Buchstaller, H P]] | ||
[[Category: Lehmann, M]] | [[Category: Lehmann, M]] | ||
| - | [[Category: Buchstaller, H.-P]] | ||
[[Category: Musil, D]] | [[Category: Musil, D]] | ||
| + | [[Category: Atp binding]] | ||
| + | [[Category: Chaperone]] | ||
| + | [[Category: Chaperone protein]] | ||
Revision as of 05:37, 30 May 2018
Estimation of relative drug-target residence times by random acceleration molecular dynamics simulation
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